The universal response of veins to insertion into the arterial circulation is the formation of intimal hyperplasia. 39% of grafts develop significant stenosis within 18 months of implantation and 40% of the remainder develop significant atheromatous lesions within 5-10 years of insertion. The goal of this proposal is to further the understanding of the basic morphological, physiological and cellular changes that occur in veins transplanted into the arterial circulation. Vein grafting into the arterial circulation results in smooth muscle cell proliferation with the formation of intimal hyperplasia. Adverse changes in endothelial function and structure appear to he one of the primary events in the formation of graft intimal hyperplasia and atherosclerosis. In concert with these changes there is a significant proliferative and synthetic response in the underlying smooth muscle cells. The aims of this proposal are to define the role of the inflammatory response (PMN, macrophages, endothelial cells, adhesion molecules and cytokines) and endothelial factors in vein graft intimal hyperplasia, to further characterize the physiology and pharmacology of endothelial and smooth muscle cells in both vein graft intimal hyperplasia and atheroma, and to determine the biology of regression of vein graft intimal hyperplasia. In addition, the proposal will investigate the utility and durability of systemic and local pharmacological and molecular control of the intimal hyperplastic response. A comprehensive approach using three vein grafts models, as well as, tissue culture systems is proposed in order to achieve these aims. The fundamental aspects of the intimal hyperplasia response will be studied in a well characterized rabbit vein graft model. Regression of intimal hyperplasia will be induced by transferring vein grafts after l4 days into the venous circulation for a further 14 days, while vein graft atheroma will be induced by feeding animals a 1% cholesterol diet. Systematic examination of vein grafts by histological, ultrastructural and immunohistochemical techniques will be carried out. Physiological and pharmacological studies will be performed using whole tissue vasomotor studies and in vitro tissue preparations. Cellular and molecular biology of the vessel wall will be studied by protein and RNA biochemistry (Western & Northern blotting, PCR and in situ hybridization). Alterations in connective tissue composition and synthesis will also be determined. Comparative studies of human vasculature and experimental grafts shall be conducted in each of these areas. The cumulative results of these data will be used to develop and test strategies for the inhibition of intimal hyperplasia. Vein grafts, as biologic conduits, have distinctive native and acquired properties which can impact significantly on subsequent performance. A greater understanding of the sequence of events in the peri-operative and post-operative phases of vein grafting will allow a clearer definition of vein graft pathophysiology. An improved understanding of the pathobiology of vein grafts will ultimately produce practical therapeutic strategies to enhance graft function, control intimal hyperplasia and extend graft patency.